It's easiest to fly into EYW (Key West Airport) but the drive from MIA or FLL can be nice. You can also get to EYW via RSW (Fort Meyers), MCO (Orlando), TPA, CLT or ATL.
Depending on how long you are going you might be able to find reasonable fare and car rentals that include a 1 way drive.
I was there a few years ago for a wedding and a bunch of us stayed at the Orchid Key Inn. It's an interior island "boutique" hotel with good rooms, a pool and bar. Easy to get to the crazier parts of the island but also quieter when you want relaxation time.